Role of JNK signaling pathway in dexmedetomidine-induced reduction of spinal neurotoxicity induced by lidocaine in rats

Abstract

Objective To evaluate the role of C-Jun N-Terminal kinase(JNK)signaling pathway in dexmedetomidine-induced reduction of spinal neurotoxicity induced by lidocaine in rats. Methods Seventy-two adult male Sprague-Dawley rats, weighing 280–320 g, in which intrathecal catheters were successfully implanted without complications, were randomly divided into 6 groups(n=12 each)using a random number table: control group(group C); SP600125(JNK signaling pathway blocker)group(group SP); dexmedetomidine group(group D); lidocaine group(group L); dexmedetomidine+ lidocaine group(group DL); SP600125+ lidocaine group(group SPL). Dimethyl sulfoxide(DMSO)20 μl was injected intrathecally in group C. SP600125 30 μg and 10% lidocaine 20 μl were injected intrathecally in SP and L groups, respectively.At 20 min after intrathecal injection of 10% lidocaine, dexmedetomidine 75 μg/kg was injected intraperitoneally in group DL, and SP600125 30 μg was injected intrathecally in group SPL.Dexmedetomidine 75 μg/kg was injected intraperitoneally in group D. The mechanical paw withdrawal threshold(MWT)and thermal paw withdrawal latency(TWL)were measured before intrathecal catheters were implanted(T0), before intrathecal administration(T1), and at 4, 8 and 12 h and 1, 2, 3, 4, 5 and 6 days after intrathecal administration(T2-10). At 24 h after intrathecal administration, 6 rats randomly selected from each group were sacrificed.The lumbar segment(L4-5)of the spinal cord was removed for detection of cell apoptosis(by TUNEL)and phosphorylated JNK(p-JNK)expression(by Western blot). The apoptotic index was calculated. Results Compared with group C, no significant change was found in the MWT, TWL, apoptotic index and expression of p-JNK in SP and D groups(P>0.05), the MWT at T2-8 in group L, at T2-6 in group DL and at T2-5 in group SPL were significantly increased, the TWL at T2-8 in group L, at T2-5 in group DL and at T2-4 in group SPL were prolonged, and the apoptotic index and expression of p-JNK were increased in DL, SPL and L groups(P<0.05). Compared with group L, the MWT was significantly decreased, and the TWL was shortened at T2-8, and the apoptotic index and expression of p-JNK were decreased in DL and SPL groups(P<0.05). Conclusion The mechanism by which dexmedetomidine mitigates spinal neurotoxicity induced by lidocaine is related to inhibited activation of JNK signaling pathway in rats . Key words: JNK mitogen-activated prorein kinaese; Lidocaine; Dexmedetomidine; Spinal cord; Drug toxicity